Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Lee, David Y. W.¹  Yang, Lu¹  Xu, Wei^2,3  Deng, Gang¹  Guo, Lin¹  Liu-Chen, Lee-Yuan^2,3 

[1] Harvard Univ, Bioorgan & Nat Prod Lab, McLean Hosp, Sch Med, Belmont, MA 02478 USA

[2] Temple Univ, Dept Pharmacol, Sch Med, Philadelphia, PA 19140 USA

[3] Temple Univ, Ctr Substance Abuse Res, Sch Med, Philadelphia, PA 19140 USA

关键词: Salvinorin A;    Kappa;    Halogenation;   

DOI  :  10.1016/j.bmcl.2010.08.001

来源: Elsevier

【 摘 要 】

Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective kappa opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3-4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at kappa (KOPR), mu (MOPR), and delta (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of alpha verses beta configuration at C-2 position. The results of KOPR binding and functional studies reveal beta isomer in general binds better than alpha isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with E-max of 46% of the kappa receptor full agonist U50,488H at 250 nM (K-i). We have also observed that the affinity to the kappa receptor increases with atomic radius (I > Br > Cl > F) which is in good agreement with halogen bonding interactions reported in the literature. (C) 2010 Published by Elsevier Ltd.

【 授权许可】

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